1. Field of the Invention
The present invention relates to encased-pellet tablets. In particular, the invention is directed to encased-pellet tablets with an outer layer that encompasses an inner core comprising plurality of coated pellets, and a method for making such encased-pellet tablets.
2. Description of the Related Technology
Interest in controlled release pharmaceutical dosage formulations has brought about increasing attention to delivery systems which employ multiple coated particles, like pellets, coated microgranules and microcapsules, where the coating on the particles can be used to control release of the active pharmaceutical ingredient (API). Controlled release may include delayed release, extended release, or repeated release. Capsules may be employed as a delivery platform for oral administration of these coated pellets or microcapsules. More recently, there is interest in finding ways to incorporate such coated pellets into a tablet. The advantages of encased-pellet oral tablets may include: (i) reduced cost and faster production; (ii) reduced vulnerability to tampering, (iii) less difficulties in esophageal transport than for capsules, and (iv) ease of swallowing.
Such a tablet may include pellets containing at least one API. Each of the pellets is individually coated with a polymer film that modifies the release profile and/or release rate of the API. The coated pellets are then formed into tablets by compression of a plurality of the coated pellets with excipients. In one method, the coated pellets are mixed with the excipients and this mixture is then compressed into tablets to provide an encased-pellet tablet where the coated pellets substantially homogenously distributed throughout the excipient matrix.
One problem that is encountered is that the compression step used to form the tablets will subject the coated pellets to a relatively large compression force. The pellet coating thus experiences large stresses, which often causes cracks or breaks in the pellet coating, which will alter the release profile and/or release rate of the API. Such tablets may thus lose at least some of the benefits of the controlled release properties of the coated pellets. Therefore, there is a need to preserve the pellet coating during tablet compression when making encased-pellet tablets.
One option for helping the pellet coating withstand the large force of tablet compression without being damaged is to strengthen the pellet coating. For example, GB 1 598 458 discloses a tablet comprising a micro-capsulated substance or a substance with a brittle coating, and a carrier that is a water-soluble, natural or synthetic wax having a melting temperature of at least 30° C. in an amount of more than 2% w/w and not more than 20% w/w, calculated based on the weight of the microcapsules or substance having a brittle coating. Polyethylene glycol (PEG) is mentioned as an example of a water soluble wax. Other carriers include microcrystalline cellulose and lactose. Example 2 of the patent produced tablets by mixing 940 mg of KCl microcapsules, 94 mg of microcrystalline cellulose, and 94 mg PEG 1000, among other components; and compressing the mixture to tablets. The KCl is encapsulated and then the KCl microcapsules are dispersed in a matrix of the carrier in the tablets. The weight ratio of microcrystalline cellulose and PEG in the tablets is 1:1.
WO 2000/50010 discloses a controlled release dosage form of the drug bupropion hydrochloride. The dosage form comprises: (a) a first pellet having a core of bupropion hydrochloride and hydroxypropyl methylcellulose, where the core is coated with a mixture of hydroxypropyl methylcellulose and PEG, which coated core is further coated with a mixture of an acrylic resin and a water soluble polymer; and (b) a second pellet which is formed by further coating the first pellet with hydroxypropyl methylcellulose, followed by an enteric coating. The enteric coating may include a polymer such as cellulose acetate phthalate or methacrylic acid copolymer. The first pellet and the second pellet may then be mixed with excipients such as crospovidone XL-10 and microcrystalline cellulose PH102 and then the mixture can be compressed into tablets.
EP 0 620 002 A1 discloses a solid pharmaceutical dosage form having an API core coated with a pharmaceutically acceptable polyalkylene glycol to reduce abrasion. The disclosed polyalkylenes include polyethylene, polypropylene and polybutylene. The API core may be a tablet having an abrasive type nature such that the tablet surface roughens and erodes during coating. Coating such tablets with a coating material comprising PEG is said to reduce abrasion during the coating process.
US 2005/0152976 A1 discloses a sustained-release formulation particle, which comprises an API and binder core coated with a coating film containing at least one cellulose based polymer and a plasticizer. The plasticizer may be polyethylene glycol, among a long list of plasticizers. The sustained-release formulation particles may be mixed with a combination of excipients such as a disintegrant and/or a swelling agent; at least one diluent; a lubricant; and optionally an antistatic agent, a permeabilizer, sweeteners, flavorings and colorants. The mixture may then be compressed to form tablets.
U.S. Pat. No. 6,923,984 discloses biologically inactive cushioning beads comprising at least one compressible cushioning component consisting essentially of a microcrystalline hydrocarbon wax or a natural wax, with the wax being at least 30% by weight of the biologically inactive cushioning beads. The biologically inactive cushioning beads may be used for making solid shaped articles (e.g. tablets) by mixing with biologically active ingredient-loaded beads and compressing the mixture to form solid shaped articles. The biologically active ingredient-loaded beads may be coated with a polymer and a plasticizer, among which plasticizers is PEG.
EP 2 510 950 A1 discloses a press-coated orally-disintegrating tablet with an outer layer surrounding an inner core. The inner core includes a powder or granular material with poor formability and contains an active ingredient. The outer layer comprises (a) microcrystalline cellulose, (b) a sugar or a sugar alcohol, and (c) one or more ingredients selected from crospovidone, starches, low-substituted hydroxypropylcellulose and carmellose. The inner core has a thickness in the range of 30 to 80% of the entire tablet.
U.S. Pat. No. 7,581,941 B2 discloses an apparatus for manufacturing a tablet with an inner core and an outer layer surrounding the inner core. The apparatus comprises a center punch and an outer punch surrounding the outer periphery of the center punch, both of which are slidable and capable of compressing. The apparatus also includes a relative position restriction means for restricting a relative position of the center and outer punches. The relative position restriction means is configured to restrict a first position in which a punch tip of the center punch is protruded from a punch tip of the outer punch and a second position in which the punch tip of the center punch is substantially coincident with the punch tip of the outer punch, and may be further configured to fail to restrict a third position in which the punch tip of the center punch is retracted within the punch tip of the outer punch.
Nicklasson et al. (“Modulation of the tabletting behaviour of microcrystalline cellulose pellets by the incorporation of polyethylene glycol,” European Journal of Pharmaceutical Sciences, vol. 9, pages 57-65, 1999) teaches pellets made by wet agglomeration of microcrystalline cellulose and PEG at a 50:50 weight ratio, followed by spheronisation. The pellets are then compressed to form tablets.
The present invention provides encased-pellet tablets that can reduce the impact of tablet compression on the pellet coating while at the same time providing desirable API release characteristics that can be tailored to particular applications. Such encased-pellet tablets may significantly reduce cracking of the pellet coating during tablet compression when compared to conventional encased-pellet tablets. Therefore, the encased-pellet tablets can be fabricated to have a drug release profile that is similar to that of the coated pellets themselves.